Retrospective Analysis of Cholera/Acute Watery Diarrhea Outbreaks in Ethiopia From 2001 To 2023: Incidence, Case Fatality Rate, and Seasonal and Multiyear Epidemic Patterns

Abstract Background The Ethiopian government has developed the multisectoral cholera elimination plan (NCP) with an aim of reducing cholera incidence and case fatality rate (CFR). To better understand and monitor the progress of this plan, a comprehensive review of national cholera epidemiology is needed. Methods Reported data on cholera/acute watery diarrhea (AWD) cases in the past 20 years were extracted from the Ethiopian Public Health Institute and World Health Organization databases. Descriptive statistics, Pearson χ2, and logistic regression analyses were conducted. Results From January 2001 to November 2023, a total of 215 205 cholera/AWD cases, 2355 deaths with a cumulative CFR of 1.10% (95% confidence interval [CI], 1.092–1.095), and a mean annual incidence rate of 8.9/100 000 (95% CI, 6.5–11.3) were reported. Two major upsurges of cholera epidemics were found in the last two decades with mean attack rate (AR) of 20.57/100 000 in 2006–2010 and 14.83/100 000 in 2016–2020. Another resurgence of outbreaks occured in 2021–2023 (mean AR, 8.63/100 000). In 2015–2023, 54.0% (53 990/99 945) of cases were aged 15–44 years. National cholera CFR (3.13% [95% CI: 2.1–4.5]) was the highest in 2022. The 2015–2023 cumulative cholera CFR was different across regions: Benishangul Gumuz (6.07%), Gambela (1.89%), Sidama (1.42%), Southern Nation, Nationalities, and Peoples’ (1.34%), Oromia (1.10%), and Amhara (1.09%). Cholera/AWD patients in older adults (≥45 years), severe dehydration, peak rainy season (June–August), and outpatients were associated with higher risk of death. Conclusions Cholera has been a public health problem in Ethiopia with case fatalities still above the global target. Case management needs to be improved particularly in outpatients and older populations. Outbreak preparedness should be rolled out well in advance of the typical rainy seasons. Significant investments are essential to advance the cholera surveillance system at healthcare setting and community level. Underlying factors of cholera deaths per areas should be further investigated to guide appropriate interventions to meet the NCP target by 2028.


INTRODUCTION
Cholera remains an important public health problem worldwide, especially in countries with limited water, sanitation, and hygiene (WaSH) and inadequate health system to detect and treat patients in a timely manner and control transmissions.The global burden of cholera remains high with an estimated 1.3 billion people at risk and an annual incidence of 2.9 million (uncertainty range: 1.3-4.0 million) and 95 000 deaths (uncertainty range: 21 000-143 000), with sub-Saharan Africa and Southern Asia accounting for 60% and 29% of the burden, respectively [1,2].The true global burden of cholera is unknown due to possible under-reporting [3].Ethiopia is one of the countries that has experienced endemic and epidemic cholera for decades [4][5][6][7].The government of Ethiopia has published the Guideline on Cholera Outbreak Management in 2011 [8] and the National Guildeline for Cholera Surveillance and Outbreak Response in 2022 [9].Since 2019, the oral cholera vaccine (OCV) has been used widely

S U P P L E M E N T A R T I C L E
by the local government in response to a series of cholera outbreaks across multiple regions in Ethiopia [10].A comprehensive multisectoral national cholera plan (NCP) has been also developed and made available since 2022 [11].Despite these government efforts, multiple cholera outbreaks have been persistently affecting local populations.However, there is lack of understanding on the trends of cholera epidemiology in Ethiopia, including national/regional outbreak patterns, incidence, case fatalities, seasonality, and underlying risk factors related to cholera deaths.It is important to identify gaps and challenges in cholera surveillance and case management in order to institute appropriate and targeted interventions.Here, we aimed to present a comprehensive overview of cholera epidemiology in the entire country during the past two decades.

Study Setting
Ethiopia is a landlocked country in the Horn of Africa located at 9.1450°N, 40.4897°E.It shares borders with Eritrea to the north, Djibouti to the northeast, Somalia to the east and northeast, Kenya to the south, South Sudan to the west, and Sudan to the northwest.Ethiopia has a total area of 1 128 571 km 2 with the population density reaching 107 people per km 2 in 2021 [12].The population size of the entire country reached over 123 million in 2022 [12].At the national level, the use of a basic water source increased from 18% in 2000 to 50% in 2016, and open defecation declined from 82% to 32% over the same period.However, in 2016, only 6% of households had access to a basic sanitation facility, and 40% of households had no handwashing facilities [13].As of 2024, the country has 12 regions and 2 city administrations.

Cholera Surveillance, Outbreak Investigation, and Reporting in Ethiopia
Cholera is a mandatory notifiable disease in Ethiopia.Continuous healthcare facility-based and community-level surveillance are implemented using the Integrated Disease Surveillance and Response system.The case detection and reporting system is according to the national guidelines developed, first in 2011 [8] and updated in 2022 [9].Prior to 2011, there was no official government document on cholera case definition or cholera surveillance system at the national or regional level.A suspected case of cholera is defined as any person ≥5 years of age with profuse acute watery diarrhea (AWD) and vomiting.A confirmed case of cholera is defined as a suspected case with Vibrio cholerae O1 or O139 isolated from stool, a sufficient threshold for an outbreak to be declared.Cholera outbreak declarations are made in cholera-epidemic areas, when a patient aged ≥5 years who develops AWD, with or without vomiting, is detected; and in an area where cholera is not known to be prevalent, when a patient aged ≥5 years who develops severe dehydration or dies from AWD is detected [8].
When a suspected cholera case is reported, a multidisciplinary outbreak investigation team-rapid response team-is organized at the Ethiopian Public Health Institute (EPHI) or district level, and an outbreak investigation initiated within 3 hours [8,9].
The recently revised National Guideline for Cholera Surveillance and Outbreak Response published in 2022 [9] incorporates significant changes compared to the previous 2011 guideline [8].The key additions to this guideline include the following: (1) OCV is integrated as a crucial component of cholera control interventions; (2) the age cut-off limit for case definition criteria has been reduced to 2 years from the previous threshold of 5 years; a patient aged ≥5 years develops severe dehydration or dies from AWD (2011 guideline), changed to ≥2 years with profuse AWD and vomiting (2022 guideline); (3) specific guidance is provided for managing cholera outbreaks within internally displaced populations, recognizing the unique challenges in such settings; and (4) the guideline underscores the importance of establishing a robust cross-border surveillance system, emphasizing the need for collaborative efforts to monitor and manage cholera outbreaks across borders [9].The term 'AWD' instead of cholera was used before 2019 [14].The determination of the case fatality rate (CFR) relies on data gathered from both facility-and community-based surveillance systems [8,9].However, the reported CFR may closely align with the fatality rate derived from facility-based data, as there is a notable risk of underreporting associated with community-based deaths.

Study Design, Data Source, and Period
A comprehensive retrospective analysis of the national cholera/ AWD outbreaks in Ethiopia in the recent 2 decades was conducted.National data on cholera/AWD from January 2001 until November 2023 was collected from the EPHI government and WHO databases, and data curation and analysis were conducted.We used the WHO cholera database [15] for the 2001-2014 incidence and CFR estimations, due to the lack of comprehensive documentation of cholera line-listing data at the national level before 2015.For calculation of incidence rates, we used annual population estimates projected by the Ethiopian Central Statistics Agency based on the 2007 national census data [16].Detailed descriptive analysis at the national and regional levels was conducted using the EPHI national cholera line-listing from January 2015 to November 2023.This dataset included basic epidemiological information such as date of cholera outbreak, age, sex, district, clinical outcome (death), level of dehydration, and diagnostic modality.

Data Analysis
Descriptive analysis was conducted to summarize the epidemiological characteristics.The annual cholera incidence rate was estimated using the total number of cholera/AWD cases per 100 000 population.The annual CFR was calculated based on the cholera deaths out of total cholera cases reported.A 5-year mean annual cholera incidence and CFR were also estimated.Bivariate and multivariate logistic regression was conducted to evaluate variables associated with CFR.Statistical analysis was performed using SPSS version 26 software.

Ethical Consideration
This study used the already available secondary aggregated public health surveillance data.Therefore, no institutional review board approval was necessary, sought, or obtained.

Descriptive Epidemiological Characteristics of Reported Cholera/AWD Cases From 2001 to 2023
In the last 2 decades, 215 205 cholera/AWD cases and 2355 deaths with a cumulative CFR of 1.10% (95% confidence interval [CI]: 1.092-1.095)were reported (Table 1).The highest case counts were reported during 2006,2007,2009,2016,2017, and 2023 with >20 000 AWD/cholera cases per year; followed by the outbreak in 2020 that recorded >15 000 cases.In the recent 5 years, the highest number of cases was reported in 2023 with nearly 30 000 cases.

Descriptive Epidemiological Characteristics of the Recent 2015-2023 Cholera/AWD Cases
Between 1 January 2015 and 30 November 2023, a total of 99 945 cases and 1030 deaths were reported per the EPHI national cholera line-listing (Table 2).Of these 99 945 cases, 55 299 (55.3%) were male.In terms of the age-stratified cases reported during this period, 53 990 (54.0%) were aged between 15 1B), cholera cases were reported throughout the year, but more in June-August (Kiremt; summer with a major rainy season all over the country) with 43.3% (43 236/99 945) of cases reported in this season during 2015-2023.Next, September-November (Mehir; spring with a relative dry season) and March-May (Belg; spring with a relative rainy season in some parts of the country) exhibited 25.6% (25 594/99 945) and 21.0% (21 015/ 99 945) of cases, respectively.December-February (Bega; autumn with a dry season) showed relatively lower number of cases (10 100/99 945 [10.1%]).The epidemiological curve (Figure 1A) exhibited persistent cholera outbreaks throughout the year (especially in 2016, 2017, 2020, and 2023) or outbreaks controlled and limited to few months (in 2018 and 2021).In those years where cholera persisted throughout the entire year, the weekly reported cases exceeded 500 (Figure 1A).
The highest number of cholera cases was reported from the Oromia (22 688/99 945 [22.7%]),Southern Nation, Nationalities, and Peoples' (SNNPR; 20 119/99 945 [20.1%]),Somali (19 010/99 945 [19.0%]), and Amhara (13 366/99 945 [13.4%]) regions, followed by Addis Ababa (7903/99 945 [7.9%]) (Table 2).Regional distribution of cholera cases had heterogeneous temporal and spatial features (Figure 2).The northern and central regions (Amhara, Afar, Tigray, and Addis Ababa) reported cases only till 2019 and were endemic, except in Addis Ababa.However, in the southern and eastern   parts (Oromia and Somali regions), it was endemic throughout the study periods.In 2023, the cholera outbreak involved all regions, except Addis Ababa and Gambela.Cholera cases were persistently reported throughout the year in some regions such as Oromia, SNNPR, and Somali in the 2017, 2020, and 2023 outbreaks.The highest number of cases were reported in 2016, 2017, and 2023 with >1000 cases weekly, and the lowest number of cases were reported during 2021 and 2022 with <100 cases per week (Figure 2).During the outbreak years, cholera peaked in the major rainy season of June-August (Kiremt) and reached the lowest during the dry season of December-February (Bega).The 2021 and 2022 outbreaks also occurred following the rainy season after cholera-free periods (Figure 1B).The trend showed its endemic nature with cases reported in each year with different magnitude and persistence.

Determinants of Cholera CFR
During the multivariate logistic regression analysis to identify the CFR risks, we found that after adjusting for age, treatment modality, dehydration level, and outbreak season, the odds of death from cholera decreased by 20% for female compared to male (adjusted odds ratio [AOR], 0.79 [95% CI: .69-.89]) reported cases (Table 5).Cholera/AWD patients in older adults aged ≥45 years (AOR, 1) were at higher risk of deaths compared to the younger age groups.Those aged 5-14 years (AOR, 0.55 [95% CI: .45-.66]) and 15-44 years (AOR, 0.41 [95% CI: .35-.48]) were nearly 50% less likely to die due to cholera compared to older age groups.Similarly, patients with clinical manifestation of no or some dehydration were nearly 70% less likely to die than those with severe dehydration (AOR, 1): no dehydration (AOR, 0.13 [95% CI: .09-.18]), and some dehydration (AOR, 0.23 [95% CI: .19-.28]).In terms of seasonality, we found that the highest cholera CFR was reported during the peak outbreak seasons.Compared to the December-February season with lower cholera cases, March-May (AOR, 1.89 [95% CI: 1.43-2.49]),June-August (AOR, 1.63 [95% CI: 1.25-2.13]),and September-November (AOR, 1.50 [95% CI: 1.14-1.99])reported over 50% risk of death related to cholera.Patients treated at the outpatient level had higher risk of mortality (AOR, 1.40 [95% CI: 1.19-1.64])than those admitted to a cholera treatment center.We investigated the possible CFR risk difference of recent years after observing the recent high CFR.During 2019-2023, the magnitude and identified risk factors associated with cholera CFR were similar to the above findings, except in the treatment modality.In the recent years, the risk of death in cholera outpatient treatment modality was >2 times (AOR, 2.69 [95% CI: 1.99-3.62])(Table 5).

DISCUSSION
The cholera outbreak patterns in Ethiopia showed annual cases persistently during the past two decades, except for 4-5 cholera-free years over ten years ago.Similar outbreak patterns were reported in neighboring South Sudan, where three epidemic waves were reported during 2014-2017 with periods of no cases between waves [17].This alludes to possible cross- border transmission and the importance of controlling cholera in nearby countries through a coordinated intervention strategy.Since 2015, cholera outbreaks have been reported every year with different magnitude.Cholera peaks during 2016-2017 in Ethiopia were associated with the 2015-2016 El Niño effect, which also affected other countries in Africa especially the East African region [18].In line with the recent global cholera resurgence after several years of decline [19], cholera cases increased again in Ethiopia in 2023 particularly during the major rainy season of June-August, lasting around 29-39 epi-weeks annually.The cholera cases in 2021-2022 were reported after the major rainy seasons, which may be associated with fecal contamination of drinking water source due to flooding.Strengthening cholera prevention interventions before the rainy season is critical.Larger cholera attack rates were considered to be associated with longer epidemic durations [20].We found similar patterns whereby persistent cholera outbreaks were shown throughout the epi-year when over 200 and 500 cases per week at regional-and nationallevels respectively were reported.This could be a proxy indicator for a prolonged outbreak, and appropriate resource allocations and cholera control interventions should be thought through.
We observed two distinct upsurges in the mean incidence of cholera/AWD during the years 2006-2010 and 2016-2020, and recent epidemics were reported in 2019-2023.In response to the recent outbreaks, the Ethiopian government has conducted several reactive mass OCV vaccination campaigns since 2019.As part of the global cholera elimination target by 2030, the Ethiopian NCP was developed and has been implemented since 2022 [11].Further research is warranted to evaluate the impact, effectiveness, and efficiency of the various interventions implemented in order to better understand their associations with cholera outbreak controls and preventions.During the COVID-19 pandemic and the cholera outbreaks in 2020-2021, the COVID-19 preventive interventions such as the promotion of hand washing and hygiene, physical distancing, and banning of gatherings could have contributed to the relatively lower number of cholera cases in these years.However, this needs to be investigated properly as there could have been also many unreported or underreported cases of cholera [21], especially if local populations had modified cholera-associated healthcare-seeking behavior during the COVID-19 pandemic per different regions of the country.
The cholera CFR is an indicator of the quality of cholera case management, and the recommended level is <1% [22].We found a cumulative CFR of 1.09% for the past 2 decades (2001-2023), 1.03% for 2015-2023, and an increased cumulative CFR of 1.87% for 2021-2023 in Ethiopia.Global cholera   mortality has been increasing in Africa; from 8.7/100 000 in 1990 to 11.3/100 000 in 2019 with a 1.2% annual increment [23].The cholera CFR in Ethiopia has not yet reached the NCP target, which aimed a 30% decrease by 2023 compared to the baseline of 1.8% [11,24].The highest cholera CFR (3.13%) in Ethiopia occurred during the 2022 outbreak and the CFR varied per regions.Cholera CFR tend to be higher at the early phase of outbreak according to a study in Haiti [25] and different across districts as shown in Uganda [26].We further found that people age ≥45 years, followed by age <5 years, severe dehydration, outpatient level management, and rainy season outbreaks were the high risk factors associated with cholera CFR in Ethiopia.A study in Uganda also showed that older age groups had a higher mortality rate than younger age groups [26].It is well known that the cause of death related to cholera is severe dehydration [27].Our finding has programmatic advantages in terms of resource allocation.Prioritizing older patients in vaccination programs could be one strategic approach, especially in areas with high cholera CFR in older age groups, if OCV doses are in shortage.Preparation for future cholera outbreaks should be planned sufficiently before the major rainy season in Ethiopia each year to effectively reduce the cholera related deaths.Community awareness and engagement for active case finding and referral to cholera treatment center/ unit or health centers are important to contain outbreaks and for timely case management [28].In our Ethiopia Cholera Control and Prevention (ECCP) project, local populations in Shashemene area had relatively good knowledge and disease perception towards cholera [29].Areas such as this, where cholera has been endemic and persistently reported may contribute to the high level of community awareness on cholera.The nonhospitalized cholera case management needs to be revisited to reduce the cholera deaths among outpatients.Appropriate cholera diagnostic capacity should be guaranteed at health centers or cholera treatment centers/units close to the affected areas, and follow-up of outpatients at the community level needs to be considered to reduce the CFR in this patient group.Sustainable resources are required to strengthen cholera surveillance system, including early case detection, health information management and reporting, laboratory confirmation and prepositioning of supplies such as RDT kits, laboratory supplies, and oral rehydration solution (ORS).
This study has some limitations.First, we used the WHO incidence and CFR gross data before 2015.This limited us in assessing the detailed epidemiological characteristics of the   outbreaks in those earlier years.Second, the reported cases might not reflect the true cholera incidence in Ethiopia due to underreporting.Third, seasonality was analyzed based on typical four major seasons in Ethiopia, but historical climate records on droughts and floodings were not considered in our analysis.Fourth, we only presented the cholera CFRs at regional-and national-levels without any investigations on the causes of CFR variations between regions.Further research is recommended on the region/district/site-specific cholera case management practice and outbreak control and preventive interventions to identify the critical gaps and pathways toward reducing cholera-related deaths.

CONCLUSIONS
Cholera is an important public health concern in Ethiopia.In the past two decades, two major upsurges of cholera epidemics (2006-2010 and 2016-2020) and another resurgence of outbreaks in 2021-2023 were noted, with the highest cholera CFR.Cholera case management needs to be improved particularly in outpatients and older populations.Cholera outbreak preparedness programs should be rolled out well in advance of the typical rainy seasons.Significant investments are essential to advance the cholera surveillance system at healthcare setting and community level.Underlying factors of cholera deaths per areas should be further investigated to guide appropriate interventions to meet the NCP target by 2028.

b
Spring with a relatively rainy season in some parts of the country.c Summer with a major rainy season all over the country.d Spring with a relatively dry season.e Autumn with a dry season.Retrospective Analysis of Cholera/Acute Watery Diarrhea Outbreaks in Ethiopia From 2001 To 2023 • CID 2024:79 (15 July) • S11 and persisted in Afar region in 2016-2017, peaked in 2018, and phased out in 2019; peaked in Addis Ababa in 2016 and another outbreak in 2019; started in Somali region in 2015, peaked in 2016-2017, and reoccurred in 2019-2023; peaked in Harari region in 2016 and reoccurred in 2019 and 2023; and hit Gambela region in 2020 (Table

Figure 1 .
Figure 1.Cholera epidemic curves and seasonal patterns in Ethiopia.A, Successive cholera epidemic waves in Ethiopia every year from 2015 to 2023.The presented epi-weeks exhibit the magnitude and persistence of cholera outbreaks in the country.B, Seasonal pattern of cumulative cholera case counts reported by the major seasons in Ethiopia from 2015 to 2023.

Figure 2 .
Figure 2. Cholera epidemic curves per region and years in Ethiopia.Graphs show the distributions of cholera cases per year and epi-weeks in each region of Ethiopia during 2015-2023.Abbreviation: SNNPR, Southern Nation, Nationalities, and Peoples' Region.

Figure 3 .
Figure 3. Annual and mean cholera incidence in Ethiopia.A, Annual trends of cholera incidence per 100 000 population in Ethiopia during 2015-2023.B, Trend of mean cholera incidence per 5-year period during 2001-2023 in Ethiopia.Abbreviation: AR, attack rate.

Figure 4 .
Figure 4. Annual and mean cholera case fatality rate in Ethiopia.A, Annual trends of cholera case fatality rate (CFR) in Ethiopia during 2015-2023.R 2 is the coefficient of determination and the best trendline determined using Expon.(CFR [%], exponential trendline).B, Trend of mean cholera CFR per 5-year period during 2001-2023 in Ethiopia.

Table 2 . Descriptive Epidemiological Characteristics of Cholera Cases in Ethiopia During 2015-2023
aThe low number of cases reported in 2021-2022 may be due to the coronavirus disease 2019 (COVID-19) pandemic measures, such as social distancing, and the overstretched health system and surveillance capacity.